Engagement of the cellular receptor for glycoprotein B of human cytomegalovirus activates the interferon-responsive pathway

Cells respond to contact with human cytomegalovirus (HCMV) virions by initi ating intracellular signaling and gene expression characteristic of the int erferon (IFN)-responsive pathway. Herein, we demonstrate that a principal m echanism of HCMV-induced signal transduction is via an interaction of the p rimary viral ligand, glycoprotein B (gB), with its cellular receptor. Cells incubated with a purified, soluble form of gB resulted in the transcriptio nal upregulation of IFN-responsive genes OAS and ISG54 (encoding 2'-5' olig oadenylate synthetase and an IFN-stimulated gene product of 54 kDa) to a co mparable level as virions or IFN. Gene induction was an immediate and direc t response to gB which did not require de novo protein synthesis. Neither t he initial virus attachment site, heparan sulfate proteoglycans, nor the IF N-alpha/beta or IFN-gamma receptors are involved in the response. Pleotropi c protein phosphorylation was required for cellular gene induction, and the mitogen-activated protein kinases ERK1 and ERK2 were activated in response to the ligand. Together these data indicate that a principal means by whic h cytomegalovirus induces intracellular signaling and activation of the int erferon-responsive pathway is via an interaction of gB with an as yet unide ntified, likely novel cellular receptor that interfaces with the IFN signal ing pathway.